Fused pyridazine compounds and their pharmaceutical use

ABSTRACT

Fused pyridazine compounds ##STR1## wherein R 1 , R 2 , R 3  and R 4  are the same or different and respectively hydrogen, a halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, and alkyl, an alkoxy or an alkanoylamino; one of R a  and R b  is a group of the formula 
     
         --O--Y--NR.sup.5 R.sup.6 
    
     wherein R 5  and R 6  are the same or different and respectively hydrogen, an alkyl, a phenylalkyl or a substituted phenylalkyl or a group forming a heterocycle together with the adjacent nitrogen atom and Y stands for a straight- or branched-chain alkylene which may have hydroxy group as a substituent on the chain, and the other is hydrogen, or both of R a  and R b  are the same or different and respectively a group of the formula 
     
         --O--Y--NR.sup.5 R.sup.6 
    
     wherein R 5  and R 6  are of the same meanings as defined above; W is ═CH-- or ═N; X is CH 2 , S, SO, SO 2  or O; and the bond designated by a broken line in its part stands for a single bond or a double bond, or their pharmaceutically acceptable salts or hydrates and their pharmaceutical use. 
     Said compounds possess stimulating effects on phagocytosis of leukocytes and macrophages, restorative effects on leukopenia, protective effects against infection, antitumor actions and the like and thus they are useable for the prophylaxis or therapy of human diseases accompanied by immunodeficiency.

TECHNICAL FIELD

This invention relates to fused pyridazine compounds or theirpharmaceutically acceptable salts or hydrates and the pharmaceuticaluse.

BACKGROUND ART

Heretofore, there have been known8-amino-4,4a,5,6-tetrahydro-2H-benzo[h]cinnolin-3-one possessingplatelet aggregation-suppressing actions, vasodilating actions,antiulcer actions and so on in Japanese Patent Application Laid-open(Kokai) No. 47468/1986; benzo[h]cinnoline derivatives possessinganxiolytic actions, platelet aggregationsuppressing actions, diureticactions and antidotal actions against administration of an excessiveamount of anxiolytics in Kokai No. 56169/1986;benzothiopyrano[4,3-c]pyridazine compounds possessing anxiolytic actionsor antidotal actions against administration of an excessive amount ofanxiolytics in W087/04162 and (1)benzopyrano[4,3-c]pyridazin-3-onecompounds in Bulletin of the Chemical Society of Japan, vol. 55, pp.2450-2455 (1982) respectively as fused pyridazine compounds exhibitingpharmacological activities.

Meanwhile, there is a growing trend toward increase of human diseaseswhich are caused by disorders in immune function such as autoimmunitydiseases, infectious diseases, immuno-deficiency diseases and so on.

It is known that an adrenal cortical hormone which is one of thewidely-used therapeutic medicines for the immune disorder diseasesexhibits a drastic effect thereon, while it brings about serious sideeffects such as immune function deficiency, infectious diseases andedema.

The object of this invention resides in providing compounds with lowlevel of side effects, which are useful for the prophylaxis and therapyof various diseases associated with immune function deficiency.

DISCLOSURE OF INVENTION

As a result of the present inventors' studies, they found that the fusedpyridazine compounds having aminoalkoxy substituents exhibited not onlyexcellent immune functionimproving actions but also infection-phylacticactions and antitumor actions, and besides have few side effects and areextremely safe in the aspect of toxicities, which resulted in thecompletion of this invention.

This invention relates to the fused pyridazine compounds of the generalformula ##STR2## wherein R¹, R², R³ and R⁴ are the same or different andrespectively hydrogen, a halogen, hydroxy, nitro, amino, cyano,trifluoromethyl, an alkyl, an alkoxy or an alkanoylamino; one of R_(a)and R_(b) is a group of the formula

    --O--Y--NR.sup.5 R.sup.6

wherein R⁵ and R⁶ are the same or different and respectively hydrogen,an alkyl or a phenylalkyl or a substituted phenyalkyl a group forming aheterocycle together with the adjacent nitrogen atom and Y stands for astraight- or branched-chain alkylene which may have hydroxy group as asubstituent on the chain, and the other is hydrogen, or both of R_(a)and R_(b) are the same or different and respectively a group of theformula

    --O--Y--NR.sup.5 R.sup.6

wherein R⁵ and R⁶ are of the same meanings as defined above; W is ═CH--or ═N--; X is CH₂, S, SO, SO₂ or O; and the bond designated by a brokenline in its part stands for a single bond or a double bond, or theirpharmaceutically acceptable salts or hydrates and their pharmaceuticaluses.

Throughout the present specification, the halogen means chlorine,bromine, fluorine or iodine; the alkyl means straight- or branched-chainalkyl having 1-8 carbon atoms such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl or octyl; the alkoxymeans a straight- or branched-chain alkoxy having 1-8 carbon atoms suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,pentyloxy, hexyloxy or octyloxy; the phenylalkyl means a phenylalkyl inwhich the alkyl moiety is a straight- or branched-chain having 1-4carbon atoms such as benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl or 4-phenylbutyl; the substituted phenylalkyl is aphenylalkyl having, on the phenyl ring, 1 to 3 substituent(s) selectedfrom halogens, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyls,alkoxys and alkanoylaminos; the heterocyclic group formed together withthe adjacent nitrogen atom means a 5- or 6-membered heterocyclic groupsuch as 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl,4-substituted-1-piperazinyl (the substituent being an alkyl, ahydroxyalkyl, a phenylalkyl, a substituted phenylalkyl, phenyl or asubstituted phenyl); the alkylene means a straight- or branched-chainalkylene having 1-8 carbon atoms such as methylene, ethylene,trimethylene, tetramethylene, propylene, hexamethylene or octamethylene;the hydroxy-substituted alkylene means 1-hydroxyethylene,1-hydroxytrimethylene or 2-hydroxytrimethylene; the alkanoylamino meansan alkanoylamino having 2-5 carbon atoms such as acetylamino,propionylamino, butyrylamino, pivaloylamino or valerylamino.

As the pharmaceutically acceptable salts of the compounds of the generalformula (I), mention is made of acid addition salts of inorganic acids(hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, etc.) or organic acids (maleic acid, fumaric acid,malic acid, succinic acid, citric acid, tartaric acid, acetic acid,lactic acid, methanesulfonic acid, p-toluenesulfonic acid, pamoic acid,etc.) or their quaternary salts. As the hydrates thereof, mention ismade of monohydrate, hemihydrate, sesquihydrate, dihydrate and the like.

When the compounds (I) of the present invention have an asymmetriccarbon atom, they can be obtained as the racemic mixtures or theoptically active isomers. When the compounds (I) have at least twoasymmetric carbon atoms, they can be obtained as the individualdiastereomers or the mixtures thereof. The present invention encompassesthese mixtures and their individual isomers. This invention alsoencompasses stereoisomers.

As the preferable compounds of this invention, there may be mentionedthe compounds of the general formula (I) wherein R_(a) is --O--Y--NR⁵ R⁶and R_(b) is hydrogen or their pharmaceutically acceptable salts orhydrates, more preferably the compounds of said compounds wherein X isCH₂ or S. As the particularly preferable compounds of the presentinvention, mention may be made of9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,9-fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,9-fluoro-2-[4-(2-methylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,9-fluoro-2-[4-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,2-[4-(3-dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one,9-fluoro-2-[3-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,9-fluoro-2-[3-(2-methyl-3dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]-cinnolin-3(2H)-one,2-[4-(2-diethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one and9-fluoro-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand their pharmaceutically acceptable salts and hydrates.

The compounds of the general formula (I) in the present invention can besynthesized, for example, by the following methods.

Method (1)

A method which comprises reacting a compound of the general formula##STR3## wherein one of R_(a) ' and R_(b) ' is hydrogen or a group ofthe formula:

    --Y--NR.sup.5 R.sup.6

and the other is hydroxy, or both mean hydroxy; R^(1') R^(2'), R^(3')and R^(4') mean a substituent or an atom as defined above for R¹, R², R³and R⁴ respectively except hydroxy; and the other symbols are as definedabove, with a compound of the general formula

    Q--Y--NR.sup.5 R.sup.6                                     (III)

wherein Q is a halogen or an active ester of an alcohol such asmethanesulfonyloxy or p-toluenesulfonyloxy and the other symbols arerespectively as defined above.

The reaction usually proceeds in a suitable solvent (an alcohol such asmethanol, ethanol or isopropyl alcohol, benzene, toluene, xylene,tetrahydrofuran, dimethylformamide, dimethylacetamide, etc.) in thepresence of a deacidifying agent (sodium methoxide, sodium ethoxide,sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide,potassium carbonate, sodium carbonate, etc.) at room temperature orunder reflux of the solvent used in 1-20 hours.

Method (2)

A method which comprises reacting a compound of the general formula##STR4## wherein one of R_(c) and R_(d) is 2,3-epoxypropoxy and theother is hydrogen, or both of them are 2,3-epoxypropoxy and the othersymbols are as defined above, with an amine compound of the generalformula

    HNR.sup.5 R.sup.6                                          (V)

wherein each of the symbols is as defined above. The reaction usuallyproceeds in a suitable solvent (an alcohol such as methanol, ethanol orisopropyl alcohol, dimethylformamide and dimethylacetamide, etc.) atroom temperature or under reflux of the used solvent in 1-20 hours.

Method (3)

A method which comprises reacting a compound of the general formula##STR5## wherein each of the symbols is as defined above, with ahydrazine compound of the general formula ##STR6## wherein each of thesymbols is as defined above, or a hydrate or an acid addition saltthereof to give a compound of the general formula ##STR7## wherein eachof the symbols is as defined above, which is subjected to ring-closurereaction.

The reaction usually proceeds in a suitable solvent (an alcohol such asmethanol, ethanol or propanol) while heating under reflux for 5-20 hoursto yield a compound of the general formula (I) or a compound of thegeneral formula (VIII).

When the hydrazine derivative of the general formula (III) is an acidaddition salt, the reaction is conducted in the presence of andeacidifying agent (sodium acetate, potassium acetate, sodiumhydrogencarbonate, sodium carbonate, potassium carbonate, etc.). When acompound of the general formula (VIII) is obtained, the correspondingcompound of the general formula (I) can be prepared by heating underreflux in acetic acid for 5-10 hours.

Method (4)

In the case of a compound of the general formula (I) wherein R_(a)stands for --O--Y--NR⁵ R⁶ :

A method which comprises reacting a compound of the general formula##STR8## wherein R⁷ is hydrogen or alkyl, Z is a straight- orbranched-alkylene and the other symbols are as defined above, with acompound of the general formula (V) or an acid addition salt thereofunder reductive conditions or subjecting the condensed product thereofto reduction reaction to produce a compound of the general formula##STR9## wherein each of the symbols is as defined above.

The reaction preferably proceeds by reducing a compound (IX) and an acidaddition salt of a compound (V) in an alcohol solvent (methanol,ethanol, etc.) under ice-cooling to under reflux of the solvent usedwith a reducing agent (sodium cyanoborohydride, etc.), or by condensinga compound (IX) and a compound (V) in a suitable solvent to give theproduct (the Schiff base or enamine compound), followed by reduction ofthe product with a reducing agent (sodium borohydride, etc.). In thelatter case, when an alcohol solvent is used as the solvent, thereaction is preferably conducted by keeping the mixture under reflux ofthe used solvent for 1-20 hours and then adding a reducing agent underice-cooling. When benzene, toluene or the like is used as the solvent,the mixture is preferably heated under reflux for 1-20 hours,concentrated under reduced pressure and then dissolved in, for example,methanol, followed by addition of a reducing agent under ice-cooling. Inthe case of a compound of the general formula (IX) wherein X is CH₂ orO, the reaction proceeds by catalytic reduction under atmosphericpressure of hydrogen in the presence of a catalyst such aspalladium-carbon in a solvent such as ethanol in an autoclave. Acompound (IX) can be subjected to the reaction in the form of theacetal.

Method (5)

In the case of a compound of the general formula (I) wherein X is SO orSO₂ :

A method which comprises subjecting a compound of the general formula(I) wherein X is S to oxidation reaction to give the correspondingcompound of the general formula (I) wherein X is SO or SO₂.

The reaction proceeds by keeping the starting compound in a suitablesolvent in the presence of an oxidizing agent (peroxyacetic acid,peroxybenzoic acid, metachloroperoxybenzoic acid, sodium hypobromide,etc.) at a temperature ranging from 0° C. to 100° C. for 1-10 hours.When the reaction is conducted by keeping in acetic acid as the solventin the presence of hydrogen peroxide at room temperature for 1-5 hours,a compound of the general formula (I) wherein X is SO can be obtaineddominantly. A compound of the general formula (I) wherein X is SO₂ canbe obtained by keeping at 30°-100° C. for 2-10 hours.

Method (6)

In the case of a compound of the formula (I) wherein the bond in theportion indicated by a broken line is a double bond, the compound can beprepared by adding dropwise to the corresponding compound of the generalformula (I) wherein the bond is a single bond bromine in a 1-1.5 timesmolar amount at 20°-60° C. in the presence of acetic acid [Journal ofMedicinal Chemistry, vol. 14, p. 262 (1971)]or by the method whichcomprises reacting with sodium m-nitrobenzenesulfonate (Bachmann Method,British Patent No. 1168291).

Method (7)

A method which comprises converting a substituent of a group of R¹, R²,R³ or R⁴ of a compound obtained in accordance with the above-mentionedMethods (1) to (6) to another group by a conventional organic chemicalmeans.

As such means, for example, mention is made of a method which comprisesreducing nitro group to amino group, a method which comprises subjectingamino group to lower-alkanoylation, a method which comprises convertingamino group to cyano group (Sandmeyer's Reaction, Gattermann Reaction)and the like.

Method (8)

A quaternary salt can be obtained by, for example, dissolving a compoundobtained in accordance with the above-mentioned Methods (1) to (7) inacetone, adding an excessive amount of methyl iodide thereto and heatingfor 1-3 hours.

The compounds of the present invention obtained in accordance with theabove-mentioned Methods (1) to (7) can be converted into an inorganicsalt thereof such as hydrochloride, hydrobromide, sulfate, phosphate andso on or an organic salt thereof such as maleate, fumarate, malate,succinate, citrate, tartarate, acetate, lactate, methanesulfonate,p-toluenesulfonate or pamoate by treating them with an inorganic acid oran organic acid as mentioned above.

Racemic mixtures can be resolved into the desired optical isomers bymeans of fractional recrystallization of a salt of an optically activeacid or by passing them into a column filled with an optically activecarrier. The individual diastereomers can be separated by a means suchas fractional crystallization, chromatography or the like. The opticallyactive isomers can be obtained by employing the optically activestarting compounds.

The stereoisomers can be isolated by a method such as recrystallizationmethod or column chromatography method.

As the examples of the compounds (I) of this invention, mention may bemade of the following compounds besides the compounds mentioned below inworking Examples.

2-[4-(1-Methyl-2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-[4-(1-Methyl-2-dimethylaminoethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-[4-(aminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-[4-(2-Methyl-3-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-[4-(3-(1-pyrrolidinyl)propoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-[4-(3-(4-Methyl-1-piperazinyl)propoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-[4-(3-Thiomorpholinopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-[4-(1-Methyl-2-trimethylammonioethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one·iodide

2-[4-(1-Methyl-2-trimethylammonioethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one·iodide

2-(4-Methylphenyl)-9-(1-methyl-2-dimethylaminoethoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-(4-Methylphenyl)-9-(1-methyl-2-dimethylaminoethoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-(4-Methylphenyl)-9-(1-methyl-2-trimethylammonioethoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one·iodide

2-(4-Methylphenyl)-9-(2-methyl-3-dimethylaminopropoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Methoxy-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-(4-Methoxyphenyl)-9-(1-methyl-2-dimethylaminoethoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-[4-(1-Methyl-2-dimethylaminoethoxy)phenyl]-9-(1-methyl-2-dimethylaminoethoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-[4-(1-Methyl-3-dimethylaminopropoxy)phenyl]-9-(2-methyl-3-dimethylaminopropoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-(4-Fluorophenyl)-9-(2-hydroxy-3-isopropylaminopropoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-(2-Hydroxy-3-isopropylaminopropoxy)-2-(4-methylphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-9-(2-hydroxy-3-isopropylaminopropoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Chloro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Chloro-2-[4-(2-methyl-3-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Chloro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Chloro-2-[4-(2-methyl-3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Methyl-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Methyl-2-[4-(2-methyl-3-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

8,9-Dimethyl-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

8,9-Dimethyl-2-[4-(2-methyl-3-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(1-methyl-2-trimethylammonioethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one·iodide

9-Fluoro-2-[4-(2-methyl-3-trimethylammoniopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one·iodide

9-Fluoro-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-[4-(3-tert-Butylamino-2-hydroxypropoxy)phenyl]-9-fluoro-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-hydroxy-3-(1-pyrrolidinyl)propoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-hydroxy-3-piperidinopropoxy)phenyl]-5,6- dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-hydroxy-3-morpholinopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-hydroxy-3-(4-methyl-1-piperazinyl)propoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-[4-(1-Methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

2-[4-(2-Methyl-3-dimethylaminopropoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

2-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

2-[4-(3-tert-Butylamino-2-hydroxypropoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

9-Methyl-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

9-Methyl-2-[4-(2-methylaminopoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

9-Fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

9-Fluoro-2-[4-(2-methyl-3-dimethylaminopropoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

2-(4-Methylphenyl)-8(1-methyl-2-dimethylaminoethoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-(3-Methylphenyl)-8-(1-methyl-2-dimethylaminoethoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-(2-Methylphenyl)-8-(1-methyl-2-dimethylaminoethoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Hydroxy-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-(4-Hydroxyphenyl)-9-(1-methyl-2-dimethylaminoethoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-(3,4-Dichlorophenyl)-9-(1-methyl-2-dimethylaminoethoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-(1-methyl-2-dimethylaminoethoxy)-2-(2-pyridyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-(1-methyl-2-dimethylaminoethoxy)-2-(4-pyridyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

8-(2-Diethylaminoethoxy)-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

8-(3-Dimethylaminopropoxy)-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

8-(3-Morpholinopropoxy)-2-(2-pyridyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

8-(3-Dimethylaminopropoxy)-2-(2-pyridyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[3-(2-dimethylaminoethoxy)-2-pyridyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[3-(3-dimethylaminopropoxy)-2-pyridyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-[4-(1-Methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-[4-(2-Methyl-3-dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-[4-(2-Methyl-3-dimethylaminopropoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-[4-(1-Methyl-2-dimethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.6-oxide

2-[4-(1-Methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.6-oxide

2-[4-inoethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.6,6-dioxide

2-[4-(1-Methyl-2-trimethylammonioethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one·iodide

2-[4-(1-Methyl-2-trimethylammonioethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.6-oxide.iodide

9-Fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

9-Fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

9-Fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.6-oxide

9-Fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.6-oxide

9-Fluoro-2-[4-(2-hydroxy-3-dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

9-Fluoro-2-[4-(2-hydroxy-3-dimethylaminopropoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

7-Chloro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

7-Chloro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

9-Methyl-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

9-Methyl-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-(4-Methylphenyl)-9-(1-methyl-2-dimethylaminoethoxy)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyranoethoxy)phenyl]-9-(1-methyl-2-dimethylaminoethoxy)-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-(4-Chlorophenyl)-9-(1-methyl-2-dimethylaminoethoxy)-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-(4-Methylphenyl)-9-(1-methyl-2-dimethylaminoethoxy)-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-(4-Fluorophenyl)-9-(2-methyl-3-dimethylaminopropoxy)-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-(4-Methoxyphenyl)-9-(1-methyl-2-dimethylaminoethoxy)-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

9-Methyl-2-[4-(3-morpholinopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

2-[4-(3-Dimethylaminopropoxy)phenyl-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

9-Fluoro-2-[4-(2-piperidinopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-piperidinopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-morpholinopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-morpholinopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-(4-methyl-1-piperazinyl)propoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-(4-methyl-1-piperazinyl)propoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-isopropylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-isopropylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2[4-(2-(2-piperidinoethylamino)propoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(2-(2-piperidinoethylamino)propoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[4-(3-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-[4-(2-Dimethylaminopropoxy)phenyl]-2,3-dihydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-[4-(2-Dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

2-[4-(2-Dimethylaminopropoxy)phenyl]-2,3-dihydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one

2-(4-Methylphenyl)-9-(2-dimethylaminopropoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-(4-Methylphenyl)-9-(2-dimethylaminopropoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

2-(4-Methylphenyl)-9-(3-dimethylaminopropoxy)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[3-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[3-(2-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[2-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

9-Fluoro-2-[2-(2-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one

The compounds of the general formula (IV) are novel. Among the compoundsof the general formula (IV), for example, the compounds of the generalformula ##STR10## wherein each of the symbols is as defined above, canbe obtained by treating the compounds of the general formula ##STR11##wherein each of the symbols is as defined above, with sodium hydroxidein methanol, followed by reaction with epichlorohydrin at 50°-55° C.

The compounds of the general formula (X) can be obtained, for example,by demethylation of the compounds of the general formula ##STR12##wherein each of the symbols is as defined above, with the use of1-butanethiol-aluminium chloride or methionine-methanesulfonic acid inchloroform at room temperature.

The specific examples of the compounds of the general formula (IV') andthose of the general formula (X) are as follows, which are notlimitative.

Examples of the compound (IV')

2-[4-(2,3-Epoxypropoxy)phenyl]-9-fluoro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-2-one,m.p. 128°-130° C.

2-[4-(2,3-Epoxypropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one,m.p. 104°-106° C.

Examples of compound (X)

9-Fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 285°-286° C. (decomposition)

9-Hydroxy-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 280°-282° C. (decomposition)

9-Fluoro-2-(3-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, m.p. 210°-211° C.

9-Hydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 245°-246° C. (decomposition)

8-Hydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 275°-277° C. (decomposition)

8-Hydroxy-(3-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 228°-230° C.

8,9-Dimethyl-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 259°-260° C.

8-Hydroxy-2-(2-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 215°-216° C. (decomposition)

9-Chloro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 279°-280° C. (decomposition)

9-Fluoro-2-(4-hydroxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, m.p.300°-302° C. (decomposition)

9-Methyl-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-(2-Hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one

2-(4-Hydroxyphenyl)-2,3,4,4aetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one, m.p. 238°-240° C.(decomposition)

2-(3-Hydroxyphenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one,m.p. 221°-222° C.

9-Methyl-2-(4-hydroxyphenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-(4-Chlorophenyl)-9-hydroxy-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one

2-(4-Hydroxyphenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one6-oxide

The compounds of the general formula (IX) are novel compounds and theycan be obtained, for example, by reacting the corresponding phenolcompounds with a compound of the general formula

    Hal--Z--COR.sup.7                                          (XII)

wherein Hal is a halogen and the other symbols are as defined above, ina suitable solvent in the presence of a deacidifying agent (potassiumcarbonate, sodium carbonate, triethylamine, etc.).

In various .pharmacological experiments using animals carrying diseasesdue to immunodeficiency, it was shown that the compounds of the presentinvention possess stimulating actions on phagocytosis of leukocytes,stimulating actions on phagocytosis of macrophages, restorative effectson leukopenia, infection-phylactic action, antitumor actions and so on.From these actions, it follows that the compounds of the presentinvention stimulate the function of reticuloendothelial system (RES) andactivate immune responses. The compounds of the present invention areeffectively applicable to human diseases associated withimmunodeficiency. As diseases due to immunodeficiency, mention may bemade of, for example, autoimmune diseases such as allergic diseases,lupus erythematosus, chronic articular rheumatism and the like, variousinfectious diseases due to the depression in immune function, and otherhypoimmunity diseases in cancers and surgical operation. The compoundsof the present invention can be used for the prophylaxis and therapy ofthe above-mentioned diseases.

The compounds of the present invention have low toxicity and can besafely administered to patients as pharmaceuticals.

The pharmaceutical composition containing a compound of the presentinvention as the active ingredient can be orally or non-orallyadministered as they are or in forms such as tablets, granules, powders,capsules, syrups, injections or preparations for external applicationwhich are obtained by mixing them with pharmaceutically acceptablecarriers, excipients, diluents and the like.

While the dosage varies depending on age, body-weight, symptom and so onof patients, for the therapy of human diseases associated withimmunodeficiency such as autoimmune disorder and infectious diseases dueto hypoimmunity, the daily dosage per an adult is usually in the rangeof about 0.5-100 mg, which can be administered at one dose or severaldivided doses.

Below, the present invention is concretely explained by illustratingReference Examples and Working Examples, to which the present inventionshould not be limited.

REFERENCE EXAMPLE 1

To a solution of 5 g of methionine and 25 ml of methane-sulfonic acid isadded 5 g of9-fluoro-2-(4-methoxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one.After the mixture is heated to 55° C. and stirred for 2 days, thereaction mixture is poured into water. The resulting crystals arecollected and washed with ethanol to give 4.5 g of9-fluoro-2-(4-hydroxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, m.p.300°-302° C. (decomposition).

REFERENCE EXAMPLE 2

A mixture of 1.0 g of methionine, 70 ml of methanesulfonic acid and 10 gof 8-methoxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneis stirred at 55° C. for 26 hours. The reaction mixture is poured intoice-water, and the mixture is neutralized with potassium carbonate andextracted with chloroform. The extract is washed with an aqueoussolution of sodium chloride and dried over magnesium sulfate. After thesolvent is distilled off under reduced pressure, the residue is purifiedby silica gel chromatography (chloroform:methanol =10:1) andrecrystallized from chloroform methanol to give 2.7 g of8-hydroxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one aswhite crystals, m.p. 193°-194° C.

The starting 8-methoxy compounds can be obtained in the followingmanner.

A mixture of 20 g of6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-acetic acid, 10.9 g of2-hydrazinopyridine and 150 ml of ethanol is heated under reflux for 2hours. The resulting crystals are collected, whereto 50 ml of aceticacid is added. The mixture is heated under reflux for 30 minutes. Aceticacid is distilled off under reduced pressure, and water is added to theresidue. The resultant crystals are collected and recrystallized fromchloroform - ethanol to give 21.5 g of8-methoxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one aswhite crystals, m.p. 194°-196° C.

REFERENCE EXAMPLE 3

A mixture of 5 g of9-fluoro-2-(4-hydroxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, 4.5g of chloroacetone, 8.8 g of potassium carbonate and 100 ml of acetoneis heated under reflux for 9 hours. After acetone is distilled off,water and isopropyl ether are added to the residue. The resultantcrystals are collected and washed with ethanol to give 5 g of crude9-fluoro-2-[4-(2-oxopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,which is subjected to the following reaction without purification.

In the same manner,9-fluoro-2-[4-(2-oxopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one(m.p. 195°-196° C.) and2-[4-(2-oxopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one(m.p. 177°-180° C.) can be obtained.

EXAMPLE 1

To 100 ml of ethanol is added2-(4-hydroxyphenyl)-9-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,and 1 g of 85% potassium hydroxide is added to the mixture whilestirring at room temperature. After 2.5 g of1-(3-chloropropyl)piperidine is added thereto, the mixture is heatedunder reflux for 11 hours.

The reaction mixture is filtered, and the filtrate is concentrated underreduced pressure. The residue is extracted with chloroform. The extractis washed with water and dried over anhydrous magnesium sulfate. Thesolvent is distilled off under reduced pressure to give 7.5 g of a brownoily substance. This oily substance is subjected to columnchromatography, followed by conversion into its maleate to give 2.9 g of9-methyl-2-[4-(3-piperidinopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.maleate,m.p. 171°-172° C.

EXAMPLE 2

To 50 ml of methanol is added 9 g of9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,and 1.7 g of sodium hydroxide dissolved in 70 ml of methanol is added tothe mixture under stirring at room temperature. Thereto is added 13 g ofepichlorohydrin, and the mixture is heated under reflux for 2 hours.After the reaction mixture is filtered, the filtrate is concentratedunder reduced pressure and the residue is extracted with chloroform. Theextract is washed with water and dried over anhydrous magnesium sulfate.Thereafter, the solvent is distilled off to give 12.5 g of a brown oilysubstance. This oily substance is subjected to column chromatography.Isopropyl ether is added to the resulting crystals, and the crystals arecollected by filtration to give 4 g of2-[4-(2,3-epoxypropoxy)phenyl]-9-fluoro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneas white crystals, m.p. 128°-130° C.

To 30 ml of dimethylformamide is added 3 g of2-[4-(2,3-epoxypropoxy)phenyl]-9-fluoro-4,4a,5,6-hexahydrobenzo[h]cinnoline-3(2H)-one,and 12 g of isopropylamine is added thereto under stirring at roomtemperature. The mixture is stirred under heating at 30°-50° C. for 14hours. After the completion of the reaction, the solvent is distilledoff under reduced pressure and the residue is extracted with chloroform.After the extract is washed with water and dried over anhydrousmagnesium sulfate, the solvent is distilled off. The obtained crystalsare converted into its maleate to give 2.3 g of9-fluoro-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.maleate, m.p. 193°-195° C.

EXAMPLE 3

To 60 ml of dried dimethylformamide is added 5 g of9-hydroxy-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,and thereto is added 1.6 g of 60% sodium hydroxide. After the mixture isstirred at room temperature for 1 hour, 5 g of 3-dimethylaminopropylchloride is added thereto. The mixture is stirred under heating at60°-70° C. for 14 hours. After the completion of the reaction, thesolvent is distilled off and the residue is extracted with chloroform.The extract is washed with water and dried over anhydrous magnesiumsulfate. Thereafter, the solvent is distilled off. The obtained oilysubstance (7.8 g) is subjected to column chromatography to give 5.2 g of2-[4-(3-dimethylaminopropoxy)phenyl]-9-(3-dimethylaminopropoxy)-4,4a,5,6-tetrahydrobenzoh]cinnolin-3(2H)-oneas an oily substance.

To 50 ml of acetone is dissolved 5.0 g of the above-obtained substance,and 3.3 g of methyl iodide is added to the solution while stirring atroom temperature. The mixture is stirred under reflux for 10 minutes.After the completion of the reaction, the solvent is distilled off andmethanol is added to the residue and the deposited crystals arecollected by filtration. The obtained crystals are recrystallized from amixed solvent of methanol and isopropyl ether to give 2.1 g of2-[4-(3-trimethylammoniopropoxy)phenyl]-9-(3-trimethylammoniopropoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.diiodide.hemihydrateas yellow crystals, m.p. 222°-225° C. (decomposition).

EXAMPLE 4

To 60 ml of dry dimethylformamide is added 6.1 g of9-hydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,and 0.96 g of 60% sodium hydride is added thereto while stirring at roomtemperature. After stirring at room temperature for 1 hour, 2.8 g of3-dimethylaminopropyl chloride is added to the mixture. After themixture is stirred over water bath under heating at 40°-50° C. for 5hours, the reaction mixture is poured into a large amount of water,followed by extraction with chloroform. The organic layer is washed withwater and dried over anhydrous magnesium sulfate. Then, the solvent isdistilled off. The residue is subjected to column chromatography and theeluate is converted into its maleate, which is recrystallized from amixed solvent of methanol and isopropyl ether to give 7.2 g of9-(3-dimethylaminopropoxy)-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.maleate,m.p. 159°-162° C.

EXAMPLE 5

To 50 ml of dry dimethylformamide is added 4.5 g of2-(4-chlorophenyl)-9-hydroxy-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one,and 0.7 g of 60% sodium hydride is added thereto while stirring at roomtemperature. After stirring at room temperature for 1 hour and additionof 2 g of 3-dimethylaminopropyl chloride, the mixture is stirred underheating at 40°-50° C. for 3 hours. After the completion of the reaction,the reaction mixture is poured into a large amount of water and themixture is extracted with chloroform. The extract is washed with waterand dried over anhydrous magnesium sulfate. Thereafter, the solvent isdistilled off. The residue is subjected to column chromatography and theeluate is converted into its fumarate to give 0.52 g of2-(4-chlorophenyl)-9-(3-dimethylaminopropoxy)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.fumarate,as yellow crystals, m.p. 208°-210° C.

EXAMPLE 6

To 150 ml of methanol is added 15.5 g of2-(4-hydroxyphenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]-pyridazin-3-one,and a solution of 2.6 g of sodium hydroxide in 150 ml methanol is addedthereto while stirring at room temperature. To the mixture is added 14 gof epichlorohydrin,

under heating at 50°-60° C. for 8 and the mixture is stirred hours.Thereafter the solvent is distilled off. To the residue is added a 10%aqueous solution of sodium hydroxide, followed by extraction withchloroform. The extract is washed with water and dried over anhydrousmagnesium sulfate. After the solvent is distilled off, the residue issubjected to column chromatography to give 10.6 g of2-[4-(2,3-epoxypropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano-[4,3-c]pyridazin-3-oneas an oily substance.

This oily substance (2.7 g) is dissolved in 10 ml of dimethylformamideand 0.71 g of morpholine is added to the solution. The mixture is heatedover a water bath at 70° C. for 3 hours. After the completion of thereaction, the solvent is distilled off and the residue is dissolved inchloroform. The solution is washed with water and dried over anhydrousmagnesium sulfate. After the solvent is distilled off, 23% hydrochloricacid in isopropyl alcohol is added to the residue. The solvent isdistilled off, followed by addition of ethanol and isopropyl ether. Theresultant crystals are collected by filtration, washed with hot ethanoland recrystallized from a mixed solvent of methanol and isopropyl etherto give 2 g of2-[4-(2-hydroxy-3-morpholinopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano-[4,3-c]pridazin-3-one.hydrochloride,as white crystals, m.p. 136°-140° C. (decomposition).

EXAMPLE 7

To a mixture of 37 g of9-fluoro-2-[4-(2-oxopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,33 g of dimethylamine hydrochloride and 700 ml of ethanol is addeddropwise 200 ml of an ethanol solution of 10 g of sodium cyanoboronhydride while stirring under heating and reflux over the period of 2hours. After the completion of the dropwise addition, the reaction isconcentrated under reduced pressure. To the residue is added 200 ml ofwater, and then conc. hydrochloric acid is added thereto underice-cooling. After the mixture is stirred at room temperature for 1hour, it is rendered alkaline with potassium carbonate and extractedwith ethyl acetate. After the extract is washed with water and driedover magnesium sulfate, the solvent is distilled off under reducedpressure Ethanol is added to the thus obtained oily substance andfurther fumaric acid is added thereto to convert into its salt. Theresultant crystals are recrystallized from hydrous ethanol to give9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one.fumarate.

EXAMPLE 8

To a mixture of 116 g of9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand 1.2 l of acetic acid is added 116 ml of 30% hydrobromic acid--aceticacid. While the solution is heated to 50° C., a solution of 48 g ofhydrobromic acid and 200 ml of acetic acid is added dropwise over theperiod of 30 minutes. After the completion of the dropwise addition, themixture is stirred for further 30 minutes. The solvent is distilled offunder reduced pressure. Water and ethyl acetate are added to theresidue, and the mixture is rendered alkaline with potassium carbonate.The ethyl acetate layer is separated, washed with water and extractedwith an aqueous solution of hydrochloric acid. The hydrochloric acidlayer is rendered alkaline with potassium carbonate, and the resultantoily substance is dissolved in ethyl acetate, which is washed with waterand dried over magnesium sulfate. The solvent is distilled off underreduced pressure. Ethanol and fumaric acid are added to the residue toconvert it into its salt. The resultant crystals are collected byfiltration and recrystallized from water--ethanol to give9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one.fumarate,m.p. 178°-180° C.

EXAMPLE 9

By conducting reactions and treatments in the same manner as in Example1 using9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand 3-dimethylaminopropyl chloride, there is obtained9-fluoro-2-[4-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 118°-120° C.

EXAMPLE 10

A mixture of 9.3 g of9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,100 ml of acetone, 8.3 g of potassium carbonate and 7.5 g ofchloropropionaldehydediethylacetal is stirred under heating and refluxfor 5 hours. After the completion of the stirring, the solvent isdistilled off under reduced pressure. Water is added to the residue andthe mixture is extracted with chloroform and dried over magnesiumsulfate, followed by concentration under reduced pressure to give crude9-fluoro-2-[4-(3-diethoxypropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.This compound (8.2 g) is suspended in 100 ml of methanol, and whilestirring at room temperature, 10 ml of 1N hydrochloric acid is added tothe suspension. After stirring at room temperature for 1 hour, thesolvent is distilled off under reduced pressure. After addition ofchloroform to the residue, the mixture is washed with water, dried overmagnesium sulfate and concentrated. To the residue are added 100 ml ofethanol and 2.5 g of dimethylamine hydrochloride, and 1.9 g of sodiumcyanoboron hydride is added to the mixture while stirring at roomtemperature. After stirring at room temperature for 15 hours, thesolvent is distilled off under reduced pressure. Water is added to theresidue, and the mixture is extracted with chloroform. The extract iswashed with water, dried over magnesium sulfate and concentrated to givean oily substance. The thus-obtained oily substance is subjected tosilica gel column chromatography and the objective fractions arerecrystallized from isopropyl alcohol to give9-fluoro-2-(4-dimethylaminopropoxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 118°-120° C.

EXAMPLE 11

By conducting reactions and treatments in the same manner as in Example1 using9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand 1-methyl-2-dimethylaminoethyl chloride, there are obtained crudecrystals, which are subjected to silica gel column chromatography. Thecrystals obtained from fractions at earlier stage are converted intofumarate, followed by recrystallization from ethanol to give9-fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate.1/2hydrate [referred to as compound of Example 11a], m.p. 176°-179° C.(decomposition). The crystals obtained from fractions at later stage areconverted into fumarate, which is recrystallized from water to give9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate[referred to as compound of Example 11b], m.p. 194°-195° C.

EXAMPLE 12

By conducting reactions and treatments in the same manner as in Example1 using9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand 2-dimethylaminoethyl chloride, obtained is9-fluoro-2-[4-(2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate,m.p. 194°-195° C. (decomposition).

EXAMPLE 13

By conducting reactions and treatments in the same manner as in Example1 using2-(2-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one and3-dimethylaminopropyl chloride, obtained is2-[2-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate,m.p. 194°-195° C. (decomposition).

EXAMPLE 14

By conducting reactions and treatments in the same manner as in Example2 using9-fluoro-2-(2-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein place of9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein Example 2, obtained is9-fluoro-2-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.maleate,m.p. 157°-158° C.

EXAMPLE 15

By conducting reactions and treatments in the same manner as in Example1 using9-fluoro-2-(3-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein place of2-(4-hydroxyphenyl)-9-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein Example 1 and 3-dimethylaminopropyl chloride in place of1-(3-chloropropyl)piperidine, obtained is9-fluoro-2-[3(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 98°-99° C.

EXAMPLE 16

By conducting reactions and treatments in the same manner as in Example1 using9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand 2-diethylaminoethyl chloride and converting into hydrochloride,obtained is9-fluoro-2-[4-(2-diethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.hydrochloride.monohydrate,m.p. 145°-149° C.

EXAMPLE 17

By conducting reactions and treatments in the same manner as in Example12 using9-fluoro-2-(3-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein place of9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnoline-3(2H)-onein Example 12 with 2-diethylaminoethyl chloride, obtained is9-fluoro-2-[3-(2-diethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onemaleate, m.p. 151°-153° C.

EXAMPLE 18

By conducting reactions and treatments in the same manner as in Example4 using 3-morpholinopropyl chloride instead of 3-dimethylaminopropylchloride in Example 4, obtained is2-(4-methylphenyl)-9-(3-morpholinopropoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.hydrochloride.hemihydrate,m.p. 117°-120° C.

EXAMPLE 19

By conducting reactions and treatments in the same manner as in Example4 using8-hydroxy-2-(4-methylphenyl)-8-hydroxy-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein place of9-hydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onewith 3-morpholinopropyl chloride, obtained is2-(4-methylphenyl)-8-(3-morpholinopropoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.hydrochloride.hemihydrate,

m.p. 198°-200° C. (decomposition).

EXAMPLE 20

By conducting reactions and treatments in the same manner as in Example19 using8-hydroxy-2-(3-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneinstead of8-hydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein Example 19, obtained is2-(3-methylphenyl)-8-(3-morpholinopropoxy)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,m.p. 113°-114° C.

EXAMPLE 21

By conducting reactions and treatments in the same manner as in Example9 using 2-methyl-3-dimethylaminopropyl chloride in place of3-dimethylaminopropyl chloride in Example 9, obtained is9-fluoro-2-[4-(2-methyl-3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.hydrochloride,m.p. 205°-206° C.

EXAMPLE 22

By conducting reactions and treatments in the same manner as in Example9 using9-fluoro-2-(3-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnoline-3(2H)-onein place of9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnoline-3(2H)-onein Example 9 and 2-methyl-3-dimethylaminopropyl chloride in place of3-dimethylaminopropyl chloride, obtained is9-fluoro-2-[3-(2-methyl-3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate.monohydrate, m.p. 209°-210° C.

EXAMPLE 23

By conducting reactions and treatments in the same manner as in Example9 using 3-morpholinopropyl chloride in place of 3-dimethylaminopropylchloride in Example 9, obtained is9-fluoro-2-[4-(3-morpholinopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.hydrochloride.hemihydrate,m.p. 173°-1.75° C. (decomposition).

EXAMPLE 24

By conducting reactions and treatments in the same manner as in Example16 using2-(4-hydroxyphenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-onein place of9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein Example 16, obtained is2-[4-(2-diethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]-pyridazin-3-one.fumarate,m.p. 160°-163° C. (decomposition).

EXAMPLE 25

By conducting reactions and treatments in the same manner as in Example24, using2-(4-hydroxyphenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-oneand 3-dimethylaminopropyl chloride, obtained is2-[4-(3-dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzopyrano[4,3-c]pyridazin-3-one.fumarate,m.p. 216°-218° C. (decomposition).

EXAMPLE 26

By conducting reactions and treatments in the same manner as in Example11 using8,9-dimethyl-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand 1-methyl-2-dimethylaminoethyl chloride, converting into the maleateand recrystallizing, obtained is8,9-dimethyl-2-[4-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.maleate,m.p. 232°-235° C. (decomposition).

EXAMPLE 27

By conducting reactions and treatments in the same manner as in Example1 using8,9-dimethyl-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand 2-methyl-3-dimethylaminopropyl chloride and converting into thefumarate, obtained is8,9-dimethyl-2-[4-(2-methyl-3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate, m.p. 207°-209° C. (decomposition).

EXAMPLE 28

By conducting reactions and treatments in the same manner as in Example1 using9-fluoro-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand 1-methyl-2-dimethyl-aminoethyl chloride and converting into thefumarate, obtained is9-fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate.hemihydrate, m.p. 176°-179° C. (decomposition).

EXAMPLE 29

By conducting reactions and treatments in the same as in Example 1 using9-fluoro-2-(4-hydroxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one and1-methyl-2-dimethylaminoethyl chloride and converting into the fumarate,obtained is9-fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-onefumarate, m.p. 172°-174° C. (decomposition).

EXAMPLE 30

By conducting reactions and treatments in the same manner as in Example7 using9-fluoro-2-[4-(2-oxopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand dimethylamine hydrochloride, obtained is9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate,m.p. 194°-195° C. (decomposition).

EXAMPLE 31

By conducting reactions and treatments in the same manner as in Example7 using9-fluoro-2-[4-(2-oxopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand methylamine, obtained is9-fluoro-2-[4-(2-methylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.hemifumarate,m.p. 218°-220° C. (decomposition).

EXAMPLE 32

By conducting reactions and treatments in the same manner as in Example7 using methylamine instead of dimethylamine hydrochloride in Example 7,obtained is9-fluoro-2-[4-(2-methylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one.hemifumarate,m.p. 217°-219° C. (decomposition).

EXAMPLE 33

By conducting reactions and treatments in the same manner as in Example7 using9-chloro-2-[4-(2-oxopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneand dimethylamine hydrochloride, obtained is9-chloro-2-[4-(2-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.fumarate,m.p. 189°-191° C. (decomposition).

EXAMPLE 34

By conducting reactions and treatments in the same manner as in Example1 using9-fluoro-2-(4-hydroxyphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one and1-methyl-2-dimethylaminoethyl chloride, obtained is9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 35

By reacting the compound as obtained in Example 11 with1-methyl-2-dimethylaminoethyl chloride and reacting and treating in thesame manner as in Example 3, obtained is9-fluoro-2-[4-(1-methyl-2-trimethylammonioethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one·iodide.

EXAMPLE 36

By reacting with 1-methyl-2-dimethylaminoethyl chloride and treating inthe same manner as in Example 1 using the 6-oxide compound correspondingto2-(4-hydroxyphenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-onein Example 6, obtained is2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]-pyridazin-3-one.6-oxide.

EXAMPLE 37

By conducting reactions and treatments in the same manner as in Example36 using the corresponding 6,6-dioxide compound instead of the 6-oxidecompound in Example 36, obtained is2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.6,6-dioxide.

EXAMPLE 38

By conducting reactions and treatments in the same manner as in Example1 using2-(4-hydroxyphenyl)-9-methyl-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-oneinstead of2-(4-hydroxyphenyl)-9-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein Example 1 and 1-methyl-2-dimethylaminoethyl chloride instead of1-(3-chloromethyl)piperidine in Example 1, obtained is9-methyl-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.

EXAMPLE 39

By conducting reactions and treatments in the same manner as in Example38 using 2-methyl-3-dimethylaminopropyl chloride instead of1-methyl-2-dimethylaminoethyl chloride in Example 38, obtained is9-methyl-2-[4-(2-methyl-3-dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano-[4,3-c]pyridazin-3-one.

EXAMPLE 40

To a mixture of 1.4 g of8-hydroxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,1.4 g of potassium carbonate and 30 ml of dimethylformamide is added 1.3g of N-(3-chloropropyl)morpholine, and the mixture is stirred at 55° C.for 3 hours. After the completion of the reaction, water is added to thereaction mixture and the mixture is extracted with ethyl acetate. Theextract is washed with water and dried over magnesium sulfate. Thesolvent is distilled off under reduced pressure. The obtained oilysubstance is purified by silica gel column chromatography (chloroform :methanol =10 : 1) and converted into the hydrochloride in methanol,which is recrystallized from methanol to give 0.6 g of8-(3-morpholinopropoxy)-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.dihydrochloride.dihydrate as white crystals, m.p. 201°-202° C.(decomposition).

EXAMPLE 41

To a mixture of 3.6 g of2-[4-(2-oxopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one,3.3 g of dimethylamine hydrochloride and 50 ml of ethanol is addeddropwise 20 ml of a solution of 1 g of sodium cyanoboron hydride in 20ml of ethanol while stirring under heating and reflux over 1 hour. Themixture is stirred under heating and reflux for further 4 hours. Afterthe completion of the reaction, the solvent is distilled off, and waterand dilute hydrochloric acid are added to the residue. After the mixtureis left standing still for 30 minutes, it is neutralized with potassiumcarbonate and extracted with chloroform. The extract is dried overmagnesium sulfate, and the solvent is distilled off. The residue ispurified by silica gel column chromatography (chloroform:methanol =10:1) and then converted into the fumarate in acetone, which isrecrystallized from ethanol to give 3.4 g of2-[4-(2-dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.fumarateas white crystals, m.p. 171°-173° C.

PHARMACEUTICAL FORMULATION EXAMPLE 1

    ______________________________________                                        Injections (1 mg/2 ml)                                                        Formulation                                                                   ______________________________________                                        Compound of Example 7                                                                            0.05%                                                      Sodium chloride    0.9%                                                       (Distilled water for injections is added in such an                           amount as to render the total amount 100.0%)                                  ______________________________________                                    

Production method

Bulk and sodium chloride are dissolved in injectable distilled water.The solution is filtered with membrane filter (of pore diameter of 0.2μm). The amples are filled with 2 ml of the solution per ample andheat-sealed under nitrogen gas atmosphere.

The amples are subjected to high pressure vapor-sterilization at 115° C.for 30 minutes. They are put in shaded vessels to provide injections.

PHARMACEUTICAL FORMULATION EXAMPLE 2

    ______________________________________                                         Tablets containing 10 mg of bulk per tablet                                  (in total amount of 129 mg/tablet)                                            ______________________________________                                        Formulation of Plain Tablets                                                  Compound of Example 7  10.0 mg                                                Lactose                51.5 mg                                                Corn starch            20.0 mg                                                Crystalline cellulose  30.0 mg                                                Polyvinylpyrrolidone K-30                                                                            5.0 mg                                                 Talc                   3.0 mg                                                 Magnesium stearate     0.5 mg                                                 Formulation of coating agents                                                 Hydroxypropylmethylcellulose 2910                                                                    4.5 mg                                                 Polyethylene glycol 6000                                                                             0.9 mg                                                 Titanium oxide         2.7 mg                                                 Talc                   0.9 mg                                                 ______________________________________                                    

Production method

Bulk, lactose, corn starch and crystalline cellulose are mixed andkneaded with the use of an aqueous solution of polyvinylpyrrolidoneK-30. The mixture is passed through a sieve of 16 mesh and formed intoparticles.

After the obtained particles are dried with heat air circulation typedrier at 50° C. for 2 hours, they are passed through a sieve of 24 mesh.The obtained particles are mixed with talc and magnesium stearate andthe mixture is tableted into 120 mg-tablets with a pounder with thediameter of 7 mm.

Further, coating is conducted with hydroxypropylmethyl cellulose 2910,polyethylene glycol 6000, titanium oxide and talc in accordance with theconventional method to give tablets.

Below, pharmacological Experimental Examples of the present inventionare specifically shown.

EXPERIMENTAL EXAMPLE 1

Stimulating Effects on Phagocytosis of Leukocytes

In accordance with the method by Stossel [Journal of ClinicalInvestigation, vol. 51, p. 615 (1972)], the experiment was conducted.Thus, glycogen was intraperitoneally administered to ICR mice weighing30-35 g, and 3 hours after administration, leukocytes in abdominalcavity were collected. A suspension containing leukocytes at 5×10⁶leukocytes/ml was prepared. To a 200 μl of the suspension were addedtest compounds, 100 μl of mouse serum and 100 μl of non-viable yeasts(1×10⁸ yeasts/ml). The mixture was cultivated at 37° C. for 20 minutes.By observing some 200 leukocytes of the reaction mixture with microscope(by magnification of 400), the number of the leukocytes whichphagocytized at least one non-viable yeast was countered. The ratio ofthe number of phagocytic leukocytes treated with 1 mM of the testcompounds relative to that of phagocytic leukocytes of controls wasestimated by the percentage. The results are shown in Table 1.

EXPERIMENTAL EXAMPLE 2 Stimulating Effects on Phagocytosis ofMacrophages

Casein.sodium was intraperitoneally administered to rats, and 3-4 daysafter the administration, macrophages were intraperitoneally collected.The phagocytosis was estimated in the same manner as in ExperimentalExample 1. The reaction conditions were the same except that macrophageswere used instead of leukocytes. The results are shown in Table 1

                  TABLE 1                                                         ______________________________________                                        Test compound                                                                              Phagocytosis of                                                                           Phagocytosis of                                      (Example No.)                                                                              leukocyte (%)                                                                             macrophages (%)                                      ______________________________________                                         2           148         196                                                   7           195         212                                                   9           162         168                                                   11b         315         182                                                  15           195         171                                                  22           170         192                                                  24           182         188                                                  25           177         174                                                  29           198         168                                                  32           233         224                                                  ______________________________________                                    

EXPERIMENTAL EXAMPLE 3 Restorative Effects on Leukopenia

ICR mice weighing 30-35 g were intraperitoneally administered at thedose of 200 mg/kg with cyclophosphamide, and the next day, the testcompounds were orally administered at the dose of 0.3 mg/kg. On the 4thday after the administration of cyclophosphamide, leukocyte count in theperipheral blood of the mice was measured. The ratio of the number ofperipheral leukocytes of mice treated with the test compounds relativeto that of mice treated with cyclophosphamide alone was estimated by thepercentage. The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Test compound Restorative effects on                                          (Example No.) leukopenia (%)                                                  ______________________________________                                         2            149                                                              7            174                                                              9            163                                                              11b          189                                                             15            188                                                             22            153                                                             29            178                                                             ______________________________________                                    

EXPERIMENTAL EXAMPLE 4 Protective Effects against Infection inLeukopenia

Male ICR mice weighing 23-27 g aged 5 weeks were intraperitoneallyadministered with cyclophosphamide at the dose of 200 mg/kg, and 4 daysafter the administration, the Escherichia coli 0-111 strains weresubcutaneously inoculated to the mice at 1×10⁸ CFU, which was taken ascontrol groups. For the groups of mice to be treated with the drugs, thetest compounds were subcutaneously administered to the mice forconsecutive 3 days from the following day of the administration ofcyclophosphamide (CY). Seven days after the inoculation of Escherichiacoli, the survival rate of the groups treated with the drugs relative tothat of the control groups was compared. The results are shown in Table3.

                  TABLE 3                                                         ______________________________________                                                  Dosage        Survival Survival rate                                Test compound                                                                           (mg/kg,       rate     (% of CY                                     (Example No.)                                                                           subcutaneously)                                                                             (%)      treatment)                                   ______________________________________                                        11b       1             43       253                                                    0.1           27       159                                                    0.01          33       194                                          ______________________________________                                    

EXPERIMENTAL EXAMPLE 5 Protective Effects against Infection inLeukopenia

In the same manner as in Experimental Example 4, except that theEscherichia coli strains were intravenously inoculated to the mice at5×10⁷ CFU and the test compounds were also intravenously inoculated tothe mice, the experiment was conducted and the survival rates wereestimated.

                  TABLE 4                                                         ______________________________________                                                  Dosage        Survival Survival rate                                Test compound                                                                           (mg/kg,       rate     (% of CY                                     (Example No.)                                                                           intravenously)                                                                              (%)      treatment)                                   ______________________________________                                        7         0.01          48.3     193                                          11b       0.01          45.0     225                                          ______________________________________                                    

TOXICITY TEST

No occurence of death was observed when the compounds of Examples 7 and11b were administered at the dose of 100 mg/kg (intravenously), 300mg/kg (intraperitoneally) and 1000 mg/kg (orally).

From the results of the foregoing experiments, it has been shown thatthe compounds of the present invention possess excellent stimulatingeffects on phagocytosis of leukocytes and macrophages, restorativeeffects on leukopenia and protective effects against infection, andexhibit antitumor actions against IMC cancer and have extremely lowtoxicity. Thus, the compounds of the present invention stimulate thefunction of the reticuloendothelial system and activate immuneresponses, and therefore they can be administered to patientseffectively and safely as the medicines for the prophylaxis and therapyof diseases accompanied by immuno-deficiency.

While the present invention has been in detail explained in thespecification including working examples, particularly the workingexamples can be changed and modified in various ways within the spiritand scope of the present invention.

We claim:
 1. A fused pyridazine compound of the formula ##STR13##wherein R¹, R², R³ and R⁴ are the same or different and are respectivelyhydrogen, a halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, astraight- or branched-chain C₁₋₈ alkyl, a straight- or branched-chainC₁₋₈ alkoxy or C₂₋₅ alkanoylamino; R_(a) is a group of the formula

    --O--Y--NR.sup.5 R.sup.6

wherein R⁵ and R⁶, the same or different, are respectively hydrogen, astraight- or branched-chain C₁₋₈ alkyl or a phenyl-C₁₋₄ alkyl in whichthe alkyl moiety is a straight- or branched-chain or a substitutedphenyl-C₁₋₄ alkyl having, on the phenyl ring, 1 to 3 substituent(s)selected from the group consisting of halogens, hydroxy, nitro, amino,cyano, trifluoromethyl, straight- or branched-chain C₁₋₈ alkyls,straight- or branched-chain C₁₋₈ alkoxys and C₂₋₅ alkanoylaminos or agroup forming a 5- or 6-membered saturated heterocycle together with theadjacent nitrogen atom selected from the group consisting of1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl,4-substituted-1-piperazinyl wherein the substituent is a straight- orbranched-chain C₁₋₈ alkyl, a hydroxy-C₁₋₈ alkyl, phenyl, a phenyl-C₁₋₄alkyl, or a substituted phenyl-C₁₋₄ alkyl having, on the phenyl ring, 1to 3 substituent(s) selected from halogens, hydroxy, nitro, amino,cyano, trifluoromethyl, straight- or branched-chain C₁₋₈ alkyls,straight- or branched-chain C₁₋₈ alkoxys and C₂₋₅ alkanoylaminos, and Ystands for a straight- or branched-chain C₁₋₈ alkylene which may have ahydroxy group as a substituent on the chain, and; W is ═CH-- or ═N--; Xis CH₂, S, SO, SO₂ or O; and the bond designated by a broken linerepresents a single bond or a double bond, or a pharmaceuticallyacceptable salt or hydrate thereof.
 2. A compound or a pharmaceuticallyacceptable salt or hydrate thereof as claimed in claim 1 or claim 2wherein X is CH₂ or S.
 3. A compound or a pharmaceutically acceptablesalt or hydrate thereof as claimed in claim 1 which is selected from agroup consistingof9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,9-fluoro-2-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,9-fluoro-2-[4-(2-methylaminopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,9-fluoro-2-[4-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,2-[4-(3-dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one,9-fluoro-2-[3-(3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,9-fluoro-2-[3-(2-methyl-3-dimethylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,2-[4-(2-diethylaminoethoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-oneand9-fluoro-2-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.4. A pharmaceutical composition which comprises a compound of apharmaceutically acceptable salt or hydrate thereof as claimed in claim1, 2 or 3 and a pharmaceutically acceptable carrier.